GLP-1 Receptor Agonists and Constipation
GLP-1 receptor agonists do not typically cause constipation; instead, they delay gastric emptying and slow upper gastrointestinal motility, with the most common gastrointestinal side effects being nausea, vomiting, and diarrhea—not constipation. 1, 2
Primary Gastrointestinal Effects
GLP-1 receptor agonists affect the upper gastrointestinal tract through specific mechanisms:
These medications delay gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, mediated through vagal nerve pathways. 1, 2
The gastrointestinal effects include reduced phasic gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased fasting and postprandial gastric volumes—none of which promote constipation. 1, 2
GLP-1 receptors are located on the myenteric plexus and activate nitrergic and cyclic adenosine monophosphate pathways to inhibit vagal activity on the gut. 2
Clinical Gastrointestinal Side Effect Profile
The actual adverse gastrointestinal effects differ from constipation:
The most common adverse effects are gastrointestinal and transient, but these are primarily nausea, vomiting, and effects related to delayed gastric emptying—not constipation. 3
Short-acting GLP-1 receptor agonists maintain more pronounced effects on gastric emptying than long-acting formulations due to tachyphylaxis, with gastrointestinal side effects being less common with long-acting preparations. 1, 4
The American Heart Association recommends starting at low doses and titrating slowly to minimize gastrointestinal side effects, which again refers to upper GI symptoms, not constipation. 1
Mechanism Clarification
Understanding why constipation is not a typical effect:
GLP-1's effects are primarily on the stomach and upper GI tract, slowing gastric emptying and reducing appetite through central nervous system mechanisms. 5, 6
The motility effects are more pronounced in individuals with normal or rapid baseline gastric emptying, affecting the stomach rather than colonic transit. 2, 7
Effects on gastric emptying diminish with continuous exposure (tachyphylaxis), particularly with long-acting formulations. 4, 5
Clinical Implications
Patients concerned about constipation should be reassured that this is not a characteristic side effect of GLP-1 receptor agonists. 3 If constipation develops in a patient on GLP-1 therapy, alternative causes should be investigated rather than attributing it to the medication.